Targeting fibroblast activation protein for molecular imaging guided cardiac repair after myocardial infarction

• Applicant: Dr. Annika Heß
• Subject Area: Radiology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517950327

Tissue repair following cardiac injury such as myocardial infarction (MI) involves a complex sequence of inflammatory cell infiltration and activation of fibroblasts. Both processes contribute to the formation of a stable scar after MI. Excessive activity of either inflammatory leukocytes or fibroblasts in the border zone and non-infarcted territories can lead to scar expansion, adverse remodelling, and subsequent heart failure. While therapies aimed at modulating fibroblast response to tissue damage have shown potential, the necessity of scar formation suggests a requirement for precise control of targeting and timing. Such precision may be facilitated by non-invasive molecular imaging of cardiac fibroblast mobilization visualizing fibroblast activation protein (FAP). In this project, we hypothesize that molecular imaging of FAP will provide a non-invasive, myocardial tissue-specific measure of pro-fibrotic activity that is linked with the immune response to tissue damage and indicates risk for heart failure progression. Moreover, FAP-targeted positron emission tomography will monitor and guide anti-inflammatory and anti-fibrotic therapeutic interventions to optimize treatment response. To test our hypothesis, we first plan to obtain basic insight into the cellular substrate for a FAP in vivo imaging signal using in vitro cell uptake assays with different human and murine cell types. We will next implement a longitudinal in vivo molecular imaging protocol for cardiac FAP expression in mice after MI of different severities. This approach will reveal the temporal dynamics of fibroblast activation within the myocardium and establish its relationship to excessive fibrosis in non-infarcted myocardium and later cardiac functional outcome. Further, we plan to evaluate the sensitivity of FAP imaging to assess the fibroblast response to anti-inflammatory therapy, clarifying the temporal interaction between inflammation and fibrosis. Finally, we plan to generate and characterize anti-fibrotic, FAP-targeted CAR T cell therapy as the initial steps toward FAP imaging-guided anti-fibrotic therapy. This project will provide unique temporal insights into the interaction of the immune system and fibroblast activation after MI and provide a foundation for imaging-guided precision therapy to promote endogenous tissue healing and repair.

• DFG Programme: Research Grants
• Co-Investigators: Privatdozent Dr. Michael A. Morgan; Professor Dr. Axel Schambach